Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference –0·01, 95% CI –0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. National Institute of Health Research.

中文翻译：

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吉非替尼和甲氨蝶呤联合治疗输卵管异位妊娠 (GEM3)：一项多中心、随机、双盲、安慰剂对照试验

输卵管异位妊娠可导致大量发病甚至死亡。目前的治疗方法是使用甲氨蝶呤或手术。约 30% 的女性接受甲氨蝶呤治疗失败，随后需要进行抢救手术。吉非替尼是一种表皮生长因子受体抑制剂，可能会改善甲氨蝶呤的效果。我们评估了口服吉非替尼联合甲氨蝶呤与单独甲氨蝶呤治疗输卵管异位妊娠的疗效。我们在 50 家英国医院进行了一项多中心、随机、双盲、安慰剂对照试验。诊断为输卵管异位妊娠的参与者接受单剂量肌注甲氨蝶呤（50 mg/m），并随机（1:1 比例）至 7 天额外口服吉非替尼（每天 250 mg）或安慰剂。根据治疗意向分析，主要结局是通过手术干预解决宫外孕。次要结局包括异位妊娠解决的时间和严重不良事件。该试验在 ISRCTN 登记处注册，ISCRTN 67795930。2016 年 11 月 2 日至 2021 年 10 月 6 日期间，328 名参与者被分配至甲氨蝶呤和吉非替尼组 (n=165) 或甲氨蝶呤和安慰剂组 (n=163)。安慰剂组的三名参与者退出了。吉非替尼组 165 名参与者中有 50 名 (30%) 进行了手术干预，安慰剂组 160 名参与者中有 47 名 (29%) 进行了手术干预（调整后风险比 1·15，95% CI 0·85 至 1·58；调整后风险比 1·15，95% CI 0·85 至 1·58；风险差异 –0·01，95% CI –0·10 至 0·09；p=0·37)。如果没有手术干预，吉非替尼组的中位缓解时间为 28·0 天，安慰剂组为 28·0 天（次分布风险比 1·03，95% CI 0·75 至 1·40）。吉非替尼组 165 名参与者中有 5 名 (3%) 发生了严重不良事件，安慰剂组 162 名参与者中有 6 名 (4%) 发生了严重不良事件。吉非替尼组腹泻和皮疹更为常见。对于输卵管异位妊娠的女性，在肠外甲氨蝶呤中添加口服吉非替尼并不能提供优于甲氨蝶呤的临床益处，并且会增加轻微的不良反应。国家健康研究所。